This three-year project will compare the efficacy and toxicity of nortriptyline (NT) to plasma concentrations of NT and of its major metabolite 10-hydroxynortriptyline (10-OH-NT) in geriatric major depression. We hypothesize 1) that plasma 10-OH-NT and 10-OH- NT/NT ratio will be strongly correlated with depressive symptom change, and that this relationship will be negative over moderate concentrations of NT; 2) that plasma NT will be less strongly related to antidepressant response, in an inverted U shaped manner; 3) that plasma concentrations will be related linearly to toxicity; 4) that plasma 10-OH-NT will account for interindividual differences in toxicity not explained by plasma NT alone. Our preliminary data indicate that plasma 10-OH-NT, but not NT, is increased at steady state in elderly compared to younger adult patients treated with equivalent doses; further, there are extreme interindividual differences in plasma 10-OH-NT/NT ratio. 10-OH- NT is pharmacologically active and is less bound to plasma protein than is NT. Our preliminary data indicates that high plasma 10- OH-NT and 10-OH-NT/NT ratio are associated with poorer efficacy in the elderly. Further, we have reported an association between high plasma 10-OH-NT and development of cardiotoxicity in the elderly. Inpatients aged greater than 60 years with major depression who are in stable physical health will be evaluated before and during six weeks of treatment with NT. A fixed final dose will be achieved. The study will utilize appropriate methods for assessment of depressive psychopathology in the elderly. Toxic effects will be assessed using the Treatment Emergent Events Scale, neuropsychological tests sensitive to drug effects, and appropriate cardiovascular parameters. Drug concentrations will be determined by high performance liquid chromatography. The study will exploit an ideal population in which to put the utility of monitoring plasma hydroxylated metabolites to a strong test. It will provide critically needed data for geriatric clinical practice, and will have relevance to treatments of younger adults as well. These data will also have theoretical value for consideration of mechanisms of antidepressant effects and of age- related changes in pharmacodynamics.